The field of organ transplantation is facing a great conundrum; acute rejection is rare now with the advent of powerful immunosuppression drugs. Paradoxically, long-term transplant survival is also rare, and grafts are continuously lost to chronic rejection while under immunosuppression. This is a sober reminder that detrimental immune programs can still be generated under broad immunosuppression. Unfortunately, the identity of such programs, how they are generated, and how they trigger graft injury are poorly defined. This is a significant hurdle hindering long-term graft survival. We recently discovered, rather unexpectedly that when conventional Th fates (Th1/Th2) are inhibited, which applies to most immunosuppressive regimens, the costimulatory molecule OX40 becomes a powerful inducer of Th9 cells (from nave CD4+ T cells). Specifically, OX40 turns off iTregs and Th17 cells and diverts the CD4+ T cells to a Th9 phenotype via a new transcription factor Batf3. This unexpected finding suggests that OX40 may play a previously unknown role in graft injury by communicating with Th9 cells in an immunosuppressive milieu. In this application we propose that OX40 is a key regulator of Th9 cells in immunosuppressed hosts. Current drugs and protocols create an immunosuppressive milieu by inhibiting Th1/Th2 cells, which allow OX40 the opportunity to favor Th9 cells by blocking iTregs and Th17 cells. We also propose that Th9 induction may be a fundamental mechanism of chronic transplant rejection. Understanding the mechanisms of Th9 induction by OX40 and the impact of Th9 cells on transplant outcomes is the central focus of this application. We believe that the proposed studies will unravel new mechanisms of graft injury. In addition, findings from these studies will have broad impacts on other immune-mediated diseases as well, such as cancer therapies and protective immunity.